Director Sam Raimi stated in a interview with MTV he would like to have The Sinister Six built up in the coming Spider-Man movies.

David Koepp turned down the chance to write the script.

Director Sam Raimi is a fan of Morbius the Living Vampire, citing his "combination of superhero + supernatural," (Raimi had started out with horror films.) though he's recently stated, in an interview, that Morbius won't be featured. But, he will be mentioned in the coming movies. He stated there will be a New York central villain, though.

Screenwriter James Vanderbilt was signed on after impressing the studio with his focus on characterization.

Producer Grant Curtis, director Sam Raimi and actor Dylan Baker expressed interest in making the film's main antagonist the Lizard (Curtis is a fan of the character). The Lizard's alter-ego, Dr Curt Connors (played by Baker), had featured extensively in the previous films; in fact in Spider-Man 3 (2007) he was seen carrying out research on animals, which led to his fateful mutation.

Sam Raimi expressed interest in filming second unit shots in his home state of Michigan, having considered it for Spider-Man 3 (2007) before opting for the cheaper area of Cleveland, Ohio.